1. Field of the Invention
The present invention is directed to novel methods for administering compositions containing essential fatty acids for use by pregnant and/or lactating women to optimize infant neurological development, length of gestation, and birth weight and to provide improved nutritional support for women prior to, during and after lactation. Further, the invention is also directed to methods for prevention and treatment of essential fatty acid deficiencies and conditions related or derived therefrom.
2. Description of the Related Art
Essential fatty acids (EFAs) are important for all humans in general, and women specifically. Failure to ingest the appropriate amount of essential fats daily may result in improper digestion, which in turn may cause inadequate absorption of other nutritional factors, including vitamins and minerals. Additionally, the body derives its energy from triglycerides, a molecule of glycerol with three fatty acids attached. Stored fatty acids support bodily functions, and are especially important when individuals are between meals or must go without food. Furthermore, the body cannot produce all the necessary fatty acids it requires. An example of such are both linolenic and linoleic acids. Thus a failure in the intake of the proper amount of EFAs can have wide ranging negative implications. Furthermore, insufficient daily intake of EFAs can lead to various levels of failure in a woman's reproductive system.
For this reason, it is especially important in the case of women who are pregnant or breast feeding or plan to become pregnant or plan to breast feed that methods of nutritional supplementation of dietary compositions containing EFAs be developed.
All major fatty acid classes were altered in the pregnant state. Of these differences in polymorphonuclear leukocytes, oleic acid and αa-linolenic acid have been shown to significantly increase (13 and 26%, respectively) and stearic acid and arachidonic acid (AA) has been shown to significantly decrease (8 and 30%, respectively). This may suggest that attenuated PMN function in pregnancy may originate from a reduction in the available pool of cellular fatty acids. Furthermore, this reduction arises as a direct result of a pregnancy-induced shift in circulating fatty acids from polyunsaturated to monounsaturated forms. Clin Diagn Lab Immunol. 1999 Jul. 6 (4): 587–593. These shifts in circulating EFAs, have been implicated in low birth weight, shorten gestation and in the occurrence of birth defects.
Due to a new born infant's high growth rate and nutritionally dependent state upon the mother, EFAs in the mother's diet continue to be important after birth especially if the mother is to breast feed.
At some time prior to the end of pregnancy, pregnant women face the decision of whether or not to breast-feed their infants. It is estimated that over 50% of all mothers choose to breast-feed their infants. See The Merck Manual, 185:1929–1931 (16th ed. 1992). Furthermore, the number of women deciding to breast-feed appears to be on the increase, particularly in higher socioeconomic groups. Id. Most experts would agree that this increase is very desirable in view of the numerous recognized nutritional benefits for developing infants which accompany their consumption of human milk. Because of the nutritional benefits for infants, many health care providers and dietitians believe breast-feeding is sufficiently important to warrant that every effort be made to breast-feed, even if only for a short time. See Whitney et al., Understanding Nutrition, 493–504 (6th ed. 1993).
Moreover, in addition to the nutritional benefits of breast-feeding, many women simply want to breast-feed their infants for emotional or psychological reasons. However, regardless of a woman's underlying reasons for breast-feeding, her nutritional status is implicated in the decision of whether to breast-feed her child. For example, a nutritional deficiency in a woman may severely limit the quantity of breast milk which is produced or, in some cases, entirely prevent lactation from occurring.
Generally speaking, the nutritional benefits of breast-feeding stem from the unique nutrient composition and protective factors present in breast milk which promote infant health and development. Id. at 494. For example, breast milk generally contains all of the vitamins required for infant development, with the possible exception of vitamin D. Id. at 500. Further, breast milk is an abundant source of minerals and, more importantly, some minerals are present in breast milk in highly desirable ratios (e.g., the 2-to-1 ratio of calcium to phosphorus in breast milk is ideal for the absorption of calcium). Id. Breast milk also contains invaluable immunological agents, including antiviral agents such as immunoglobulins, and antibacterial agents such as lactoferrin.
In addition to the above discussed vitamins, minerals and immunological agents, breast milk also contains various “energy nutrients”. For example, breast milk contains lactose which is the carbohydrate present in breast milk and which facilitates calcium absorption. Id. A relatively small amount of protein, primarily in the form of alpha-lactalbumin, is also present in breast milk, thus placing less stress on the infant's immature kidneys. Id. Breast milk additionally contains fat along with fat-digesting enzymes. Id. Linoleic acid, a fatty acid, is found in large quantities in breast milk. Id.
The presence of EFAs in breast milk is significant for various reasons, as described below. Because the body derives most of its energy from stored triglycerides, and the body cannot make all the EFAs it requires, for example linoleic acid or linolenic acid, these indispensable EFAs must be supplied through the infant's food food. Again, EFAs are important for the developing brain, immunological system and cardiovascular system, and have some role to play in every organ of the body. Linoleic acid is the most important member of the omega-6 family of fatty acids. The body uses linoleic acid to synthesize an important 20-carbon fatty acid, arachidonic acid, which helps maintain the structural integrity of cell membranes. Linolenic acid is the most important member of the omega-3 family of fatty acids. The body requires this fatty acid to make eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Many body tissues require EPA and DHA. DHA is especially important in the retina and in the cerebral cortex of the brain. Half of the DHA in a fetus's body accumulates in the brain before birth, and half after birth, an indication of the importance of fatty acids to the fetus during pregnancy and then to the young infant during lactation.
Successful breast-feeding requires that the mother maintain good nutrition and adequate rest. A good, nutritional diet is needed to support the stamina that nursing an infant requires. Beyond this, however, a woman must consume a nutrient-rich diet to produce nutrient-rich milk.
A healthy nursing mother generally makes about 25 ounces of milk each day. To produce this milk, the mother needs to consume 650 kcalories above what she would normally require for herself. Woman are advised to eat about 500 kcalories worth of extra food and let the extra fat left over from pregnancy provide the rest. Women may not consume enough food for many reasons, including the desire to lose all of the weight gained during pregnancy. But restricting food and energy in this fashion will result in breast milk which is lacking in nutrients, low quantities of breast milk or, in the worse case scenario, no breast milk at all.
According to the medical literature, a nursing mother should eat foods high in nutrients and drink plenty of fluid. Nutritional deprivation in the mother generally reduces the quantity, more so than the quality, of the milk. So while woman can produce milk with sufficient protein, carbohydrate, fat and minerals even if their own intake is insufficient, the quality of the breast milk is maintained at the expense of the mother's own nutrient repositories. Moreover, quantities of particular vitamins, such as B6, B12, A and D, in breast milk will actually decline in response to a inadequate intakes by the mother.
Infants have different nutritional needs than those of children and adults. They require more fat and less protein than adults. Breast milk contains high concentrations of fat-digesting enzymes that allow for highly efficient fat absorption. Breast milk, as well as colostrum, contain the essential fatty acid linoleic acid. Understanding Nutrition, Whitney and Rolfe, 6th Ed., 136–40 (1993).
Full term babies who are not fed enough linoleic acid suffer from dermatosis and growth failure. These conditions are easily reversed when linoleic acid is added to the infant's diet. Fatty acid deficiency in a breast-feeding infant is a hazzard of long term low fat parental dieting. The Merck Manual, 16th Ed., 968 (1992).
Methods of administering linolenic acid to lactating females have been previously described. Specifically, Horrobin, U.S. Pat. No. 5,264,217, discloses methods for increasing the total fat content of milk, the essential fatty acid content of milk and the flow of milk during lactation, or for preventing or reducing the normal decrease in milk fat content that occurs during prolonged lactation, by administering gamma linolenic acid, dihomo-gamma-linolenic acid or their mixture to a lactating female.
Other references disclose compositions and methods that have been developed for achieving fat enrichment of ruminant milk for consumption by humans. In general, animal feed is supplemented with fatty acids. In turn, the milk produced by the ruminants is itself rich in fatty acids.
Chalupa et al., U.S. Pat. No. 5,004,728, describe a method for increasing milk yields in lactating ruminants. The ruminants are fed somatotropin and salts of long chain fatty acids. The fatty acids in the feed increases the level of long chain fatty acids in the milk produced by the ruminant. One long chain fatty acid suitable for this inventive subject matter is linoleic acid.
Nishimura et al., U.S. Pat. No. 5,635,198, describe a granular agent comprised by an active core coated by certain fatty acids and oils to be administered to ruminants. This granular agent has a superior absorption rate and results in, among other benefits, efficient lactation in the ruminant.
Scott et al., U.S. Pat. No. 3,925,560, describe a feed supplement for ruminants comprising fatty acids encapsulated with a protein-aldehyde reaction product. These fatty acid supplements, including linoleic acid, provide high energy feed supplements for ruminants. These supplements will result in the ruminate producing a milk very high in unsaturated fats.
Palmquist et al., U.S. Pat. No. 4,642,317, describe a process for feeding ruminants fatty acids in the form of their calcium salts, which are added to feed. This process would allow dairy cows to make milk high in fats, without depleting their own fatty acid stores.
Richardson, U.S. Pat. No. 5,143,737, describes a method for the modification of ruminant food so that the ruminant will produce a milk with modified fat. This method comprises a non-toxic food to be surrounded by an acid-sensitive nontoxic crosslinking material. Animals eating this composition will make milk with a higher level of unsaturated fats.
Furthermore, several prenatal supplements are available which provide pregnant women with varying amounts of vitamins and minerals. The Physicians' Desk Reference describes various vitamin and mineral supplements for use by pregnant women. For example, Nestabs® CBF, prenatal formula, available from The Fielding Company, Maryland Heights, Mo., contains 4,000 I.U. of vitamin A, 400 I.U. of vitamin D, 30 I.U. of vitamin E, 120 mg of vitamin C, 1 mg of folic acid, 3 mg of thiamine, 3 mg of riboflavin, 20 mg of niacinamide, 3 mg of pyridoxine, 8 mcg of vitamin B12, 20 mg of calcium, 100 mcg of iodine, 15 mg of zinc, and 50 mg of iron per dose. NESTABS® CBF are “expressly formulated for use during pregnancy and lactation” and are available only in tablet form. See Physicians' Desk Reference, (53d Ed., 1999) 1011.
Materna® prenatal vitamin and mineral formula, available from Lederle Laboratories, Pearl River, N.Y., contains 5,000 I.U. of vitamin A, 400 I.U. of vitamin D, 30 I.U. of vitamin E, 120 mg of vitamin C, 1 mg of folic acid, 3 mg of vitamin B1, 3.4 mg of vitamin B2, 10 mg of vitamin B6, 20 mg of niacinamide, 12 mcg of vitamin B12, 30 mcg of biotin, 10 mg of pantothenic acid, 200 mg of calcium, 150 mcg of iodine, 27 mg of iron, 25 mg of magnesium, 2 mg of copper, 25 mg of zinc, 25 mg of chromium, 25 mg of molybdenum, 5 mg of manganese, and 20 mcg of selenium per dose. Materna® is designed “provide vitamin and minerals supplementation prior to conception, throughout pregnancy and during the postnatal period for both lactating and nonlactating mothers” and is available in tablet form only. See Id. at 1522–3.
Enfamil® Natalins® RX multivitamin and multimineral supplements, available from Mead Johnson Nutritionals, Evansville, Ind., provide 4000 I.U. of vitamin A, 80 mg of vitamin C, 400 I.U. of vitamin D, 15 I.U. of vitamin E, 1.5 mg of thiamin, 1.6 mg of riboflavin, 17 mg niacin, 4 mg of vitamin B6, 1 mg of folic acid, 2.5 mcg of vitamin B12, 30 mcg of biotin, 7 mg of pantothentic acid, 200 mg of calcium, 54 mg of iron, 25 mg of zinc, and 3 mg of copper per dose. Enfamil® Natalins® RX are “to supplement the diet during pregnancy of lactation” and are available only in tablet form. See Id. at 1692.
Prenate® Ultra™ prenatal vitamins, available from Sanofi Pharmaceuticals, New York, N.Y., contain 90 mg of elemental iron, 150 mcg of iodine, 200 mg of calcium, 2 mg of copper, 25 mg of zinc, 1 mg of folic acid, 2700 I.U. of vitamin A, 400 I.U. of vitamin D3, 30 I.U. of vitamin E, 120 mg of vitamin C, 3 mg of vitamin B1, 304 mg of vitamin B2, 20 mg of vitamin B6, 12 mcg of vitamin B12, 20 mg of niacinamide, and 50 mg of docusate sodium per dose. Prenate® Ultra™ is “indicated for use in improving the nutritional status of women throughout pregnancy and in the postnatal period for both lactating and nonlactating mothers and is only available in tablet form. See Id. at 2802.
Niferex®-PN formula, available from Schwarz Pharma, Inc., Milwaukee, Wis., contains 60 mg of iron, 1 mg of folic acid, 50 mg of vitamin C, 3 mcg of vitamin B12, 4,000 I.U. of vitamin A, 400 I.U. of vitamin D, 2.43 mg of vitamin B1, 3 mg of vitamin B2, 1.64 mg of vitamin B6, 10 mg of niacinamide, 125 mg of calcium, and 18 mg of zinc per dose. Niferex®-PN is “indicated for prevention and/or treatment of dietary vitamin and mineral deficiencies associated with pregnancy and lactation” and is only available in tablet form. See Physicians' Desk Reference, (53d Ed., 1999) 2916–7.
Niferex®-PN Forte formula, available from Schwarz Pharma, Inc., Milwaukee, Wis., contains 60 mg of iron, 1 mg of folic acid, 50 mg of vitamin C, 3 mcg of vitamin B12, 5,000 I.U. of vitamin A, 400 I.U. of vitamin D, 30 I.U. of vitamin E, 80 mg of vitamin C, 1 mg of folic acid, 3 mg of vitamin B1, 3.4 mg of vitamin B2, 4 mg of vitamin B6, 20 mg of niacinamide, 12 mcg of vitamin B12, 250 mg of calcium, 200 mcg of iodine, 10 mg of magnesium, 2 mg of copper, and 25 mg of zinc per dose. Niferex®-PN is “indicated for prevention and/or treatment of dietary vitamin and mineral deficiencies associated with pregnancy and lactation” and is only available in tablet form. See Id. at 2917–8.
Advanced Formula Zenate® prenatal multivitamin/mineral supplement, available from Solvay Pharmaceuticals, Marietta, Ga., contains 3,000 I.U. of vitamin A, 400 I.U. of vitamin D, 10 I.U. of vitamin E, 70 mg of vitamin C, 1 mg of folic acid, 1.5 mg of vitamin B1, 1.6 mg of vitamin B2, 17 mg of niacin, 2.2 mg of vitamin B6, 2.2 of vitamin B12, 200 mg of calcium, 175 mcg of iodine, 65 mg of iron, 100 mg of magnesium, and 15 mg of zinc per dose. Advanced Formula Zenate® is “a dietary adjunct in nutritional stress associated with periconception, pregnancy and lactation” and is only available in tablet form. See Id. at 3128.
Precare® prenatal multi-vitamin/mineral formula, available from UCB Pharma, Inc., Smyrna, Ga., contains 50 mg of vitamin C, 250 mg of calcium, 40 mg of iron, 6 mcg of vitamin D, 3.5 mg of vitamin E, 2 mg of vitamin B6, 1 mg of folic acid, 50 mg of magnesium, 15 mg of zinc and 2 mg of copper per dose. Precare® “is indicated to provide vitamin and mineral supplementation throughout pregnancy and during the postnatal period-for both lactating and nonlactating mothers and is available only in caplet form. See Id. at 3163.
Natafort® prenatal multivitamin, available from Warner Chilcott, Rockaway, N.J., contains 1,000 I.U. pf vitamin A, 400 I.U. of vitamin D3, 11 I.U. of vitamin E, 120 mg of vitamin C, 1 mg of folic acid, 2 mg of thiamine mononitrate, 3 mg of riboflavin, 20 mg of niacinamide, 10 mg of vitamin B6, 12 mcg of vitamin B12, and 60 mg of iron per dose. Natafort® is designed “to provide vitamin and mineral supplementation throughout pregnancy and during the postnatal period, for both the lactating and non-lactating mother” and is only available in tablet form. See Id. at 3212.
However, none of the above formulations provide women with essential fatty acids in amounts and proportions necessary to optimize infant neurological development. Further, the prenatal nutritional supplements containing vitamins and minerals are entirely lacking in essential fatty acids. In the case of the enriched ruminant milk, while this milk may be a good source of fatty acids for adults, ruminant milk is not recommended for infants because even supplemented formula cannot match the immunological benefits of breast milk.
Therefore, there remains a need for a nutritional formulation which optimizes infant neurological development. It is also desirable to have nutritional formulations which prevent a woman's stores of fatty acids from becoming depleted during lactation. There is also a particular need for nutritional formulations which provide essential fatty acids in optimal ratios and amounts, along with required vitamins and minerals. Moreover, it is desirable to have formulations and methods which prepare a woman's body for the stresses imposed by lactation.